2015: This year we have focused on finalizing the transition of our laboratory from BNL to the Clinical Center at NIH, which has required development and submission of protocols for the IRB, working on the design of laboratories, hiring of new personnel and on data analyses from studies we had completed at BNL prior to moving to NIH and from the anlysis of open access data sets.. STRIATAL DOPAMINE D2/D3 RECEPTORS MODULATE VISUAL ATTENTION DURING SLEEP DEPRIVATION. Sleep deprivation (SD) impairs brain activation and cognitive performance including attention, which might reflect SD-induced reductions in dopamine D2 and D3 receptors (D2/D3R). Here we test this hypothesis. Methods: We evaluated striatal D2/D3R with 11Craclopride PET and fMRI activation during a visual attention (VA) task in 14 controls twice, during rested wakefulness (RW) and during SD (30-35 hours). The non-displaceable binding potential (BPND) was used to quantify D2/D3R in striatum and to assess the association with fMRI signals during VA. Results: VA accuracy was lower during SD than RW (P < 0.05) and D2/D3R in striatum were lower for SD than for RW (P < 0.05). fMRI activation was higher in thalamus and lower in superior parietal cortex (SPC) and prefrontal cortex (PFC) for SD than RW (PFWE < 0.05). In thalamus, SD-related reduction in striatal D2/D3R was associated with enhanced activation during SD; in SPC, the balanced CD-to-VS D2/D3R was associated with hypoactivation during SD; and in PFC, the balanced PU-to-VS D2/D3R was associated with reduced deactivation during SD. Discussion: Findings are consistent with a robust DAergic modulation of cortical and thalamic activation that is impaired by SD. MARIHUANA ABUSERS HAVE BLUNTED REGIONAL BRAIN REPSONSES TO DA. Here we tested the hypothesis that marihuana abusers would show impaired PFC activity and reduced brain reactivity to DA stimulation. Methods: We measured brain glucose metabolism (using PET and 18FFDG) at baseline (after placebo) and after methylphenidate (MP), a drug that increases DA, in controls (n=24) and marijuana abusers (n=24). Results: Brain glucose metabolism was significantly lower in marihuana abusers in PFC including anterior cingulate cortex (ACC) and in ventral striatum. MP increased whole brain metabolism in controls (p=0.04) but not in marihuana abusers and MP-induced increases were significantly larger in midbrain, BA 38, globus pallidum and midline thalamus in controls than in abusers. Discussion: The reduced baseline metabolism in PFC in marihuana abusers is consistent with findings in other addictions and the attenuated responses to MP are consistent with decreased brain reactivity to DA stimulation. REDUCED SLEEP DURATION MEDIATES DECREASES IN STRIATAL D2/D3 RECEPTORS IN COCAINE ABUSERS. Neuroimaging studies have documented reduced striatal D2/D3R availability in cocaine abusers but the mechanism(s) remain poorly understood. Here we investigated whether reduced sleep duration underlies the decreases in D2/D3R in cocaine abuse. Methods: We used PET with 11Craclopride to measure striatal D2/D3R in 24 active cocaine abusers and 21 controls. Results: Cocaine abusers had shorter sleep duration and longer periods of sleep disturbances than controls. Sleep duration predicted striatal D2/D3R and statistically mediated the relationship between cocaine abuse and low striatal D2/D3R. Discussion: These findings suggest that impaired sleep patterns contribute to the low striatal D2/D3R availability in cocaine abusers. POLYMORPHISMS IN DTNBP1) MODULATES BASELINE D2/D3R AND DA RELEASE IN STRIATUM: The DTNBP1 gene (encodes dysbindin 1) has been associated with schizophrenia, which is hypothesized might reflect its involvement in DA neurotransmission. Here, we test this hypothesis in healthy individuals. Methods: 63 controls were studies with 11Craclopride with and without a MP challenge to measure baseline D2/D3R availability and MP-induced DA increases. We selected three SNP genotypes (rs3213207, rs1047631, rs2619538) with previously established clinical relevance. Results: Baseline D2/D3R differed for Dysb1 (TT > CT) and for dysb3 (AA > AT and TT). MP-induced DA increases differed significantly across the three genotypes with the largest difference observed for dysb1 (CT > TT). Discussion: Our findings are consistent with DTNBP1 polymorphisms differentially regulating DA neurotransmission in striatum. LOCAL AND GLOBAL THALAMIC FUNCTIONAL CONNECTIVITY AFFECTED BY ACUTE AND CHRONIC ALCOHOL EXPOSURE. Acute and chronic alcohol are associated with marked reductions in brain glucose metabolism. In healthy controls differences in resting functional connectivity density (FCD) measured as local FCD (lFCD) and global FCD (gFCD) correlate with glucose metabolism. Here we explored this relationship in acute and chronic alcohol consumption. Methods: Effects of acute alcohol (ALC; 0.75 g/kg) vs. placebo (PLC) on metabolism were measured with PET and FDG and on FCD with fMRI in 24 controls (NM) and 16 heavy alcohol drinkers (HD). Results: Brain metabolism decreased during intoxication and HD showed less metabolism than NM. HD had less lFCD in medial dorsal thalamus than NM. Alcohol intoxication increased lFCD and gFCD in thalamus. Alcohol induced changes in glucose metabolism were not correlated with thalamic changes in FCD. Discussion: These findings support the notion that alcohol-induced decreases in glucose metabolism do not reflect a decrease in brain function, which would have resulted in decreases in FCD and also show that acute and chronic alcohol disrupt thalamic activity. STRUCTURAL AND FUNCTIONAL CONNECTIVITY OF PRECUNEUS AND THALAMUS TO THE DEFAULT MODE NETWORK (DMN). The thalamus and DMN are involved with consciousness. Here we evaluated the structural and functional connectivity of the thalamus to the DMN. Methods: Diffusion-weighted (DTI) and resting-state data from 37 healthy subjects was obtained from the Human Connectome Database. Parcellation maps were created using probabilistic tractography (from DTI), while resting-state functional (RFC) correlations were assessed using seed analyses between precuneus (main node of DMN) and thalamus and regins in DMN. Results: In precuneus DTI revealed that the strongest connections was with thalamus and showed minimal connections to angular gyrus (AG) whereas the RFC analyses revealed that the strongest correlation was with AG. In thalamus DTI revealed connections to hippocampus, mPFC, sFG, and precuneus but minimal connection to AG and RFC also revealed weak connectivity with AG. Discussion: Differences between structural and functional connectivity in thalamus and precuneus with DMN are likely to reflect the dynamic shifts in RFC for hub regions in brain. MAPPING VARIABILITY IN DYNAMIC FUNCTIONAL CONNECTIVITY DENSITY PATTERNS. Conventional studies on RFC MRI evaluate functional connectivity as if they were static. However, RFC experiences dynamic changes. Here we analyzed the variability of the dynamic patterns of local degree (lFCD), a measure of RFC. Methods: rfMRI datasets from 193 healthy adults from the Human Connectome Project were used and the standard deviation (sd) was used to quantify temporal variability of lFCD. Results and Discussion: lFCD and RFC patterns vary with time. Across subjects, lFCD approached a plateau as a function of time, reaching 63% of the equilibrium lFCD after 270 seconds of MRI acquisition. The amplitude of time-varying lFCD was strongest in ventral occipital, superior and posterior parietal cortices, regions that contain the most prominent brain hubs. Cortical regions and cerebellum demonstrated pronounced aging effects on&#61472;the dynamic patterns of IFCD.